Hydrazine derivatives



United States Patent 3,031,479 HYDRAZINE DERIVATIVES Otto Straub, Bottmingen, and Paul Zeller, Neuallschwil,

Switzerland, assignors to Hothnann-La Roche Nutley, NJ a corporation of New Jersey No Drawing. Filed 0st. 27,1958, Ser. No. 769,553

Claims priority, application Switzerland Get. 29, 1957 19 Claims. (Cl. 260-4045) Inc.,

This invention relates to substituted acid hydrazides of the general formula substitution products thereof, and acid addition salts of.

same.

In the above formula R may represent a saturated or unsaturated cycloaliphatic, a saturated or unsaturated, straight-chained or branched aliphatic hydrocarbon radical or one of these radicals carrying halogeno, hydroXy-, acyloXy-, alkoxyor alkylmercapto-suhstituents. Typical radicals represented by R include alkyl groups, such as lower alkyl groups, e.g methyl, ethyl, propyl, isopropyl, butyl and the like, as Well as higher homologous alkyl groups, such as tetradecyl, hexadecyl, heptadecyl and the like; halogeno-substituted alkyl groups, such as chloromethyl, bromomethyl, chloroethyl, chloropropyl and the like; hydroXy-substituted alkyl groups, such as hydroxymethyl, hydroxyethyl, hydroxypropyl and the like; acyloxy substituted alkyl groups such as acetoxyethyl, acetoxypropyl and the like; alkoxy-substituted alkyl groups, such as methoxymethyl', methoxyethyl, ethoXyet-hyl and the like; alkylmercapto-substituted alkyl groups such as methylmcrcaptomethyl, methylmercaptoethyl and the like; and cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The hydrazine derivatives of this invention may be produced by condensing 1,2-diisopropyl-hydrazine or an acid salt thereof, e.g. a hydro-halide, with an acylating agent bearing the appropriate acyl group, e.g'. an acyl halide, preferably the chloride, or an acid anhydride. Approximately equitnolecular proportions of 1,2-diisopropyl-hydrazine and acylating agent are used in thecondensation reaction. If an acyl halide is used as one'r'eactant, the reaction is preferably carried out in an inert solvent, such as benzene, in the presence of a tertiary base, such as pyridine or triethyl-amine or of an excess of 1,2- diisopropylhydrazine. AcyloXy-substituted acid hydra- Zide derivatives thus obtained may be hydrolyzed to the corresponding hydroXy-substitution products according to known methods, e.g. by treatment with a meth anolic sodium methylate solution.

The compounds of this invention react with inorganic or organic acids to form acid addition salts. Illustrative salts include those formed with mineral acids, e.g hydrohalides, such as the hydrochloride, the hydrobromide, the

3,031,479 Patented Apr. 24, i962.

logical regulators, such as serotonine, tryp'tarrn'ne, epinephrine, etc., and stimulate the central nervous system. They are useful in psychotherapy for relief of disturbed or depressed states. They are also useful for increasing weight in cases where oachexia is present. The acid hydrazide compound or a medicinally acceptable acid addition salt thereof may be administered orally or parenterally in conventional solid or liquid dosage forms, such as tablets, capsules, inject'ables, etc., comprising therapeutic doses incorporated in a conventional solid or liquid vehicle with or without excipients.

The following examples are illustrative of the invention. All temperatures are stated in degrees centigrade. Example 1 23.5 g. of acetyl chloride were added dropwise over a period of two hours, at room temperature, with strong stirring and with the exclusion of moisture, to a mixture 7 of 34.8 g. of l,2diisopropyl-hydrazine and 400" cc. of

absolute pyridine. T he mixture was stirred for an additional two hours at about Mostof the pyridine was then distilled ot't in vacuo and the residue was taken up w in 500 m. of chloroform. The mixture was then shaken- With portions of a: concentrated aqueous solution cont-aining 22 g. of potassium carbonate. The chloroformlayer Was separated and dried over sodium sulfate, then concentrated in vacuo. Theoily residue was purified by fractionating several times in vacuo. The product, l-acetyll,2 diisopropyl-hydrazine, thus obtained boiled at 88- 89/ 12 mm.

l acetyl-1,2-diisopropyl-hydrazine was treated with ethanolic-HCl to obtain l-acetyl-l,Z-diisopropyl-hydrazine hydrochloride. After crystallization from alcohol/ethe the hydrochloride melted at 15 3-155 Example 2 A solution of 24.1 g. of pivaloyl chloride in cc. of absolute benzene was added dropwise, at roonr tem perature. and with stirring, to a solution of25=.5 g. of- 1,2- diisopropyl-hydrazine in a mixture of cc. of absolute benzene and 150 cc. of absolute pyridine; was stirred for an additional 2 /2 hours at 50. The suspension thus obtained was concentrated in vacuo and the residue taken up inv chloroform. The chloroform absolute benzene was added dropwise, with stirring; to

a solution of 3-2 g. of 1',Zdiisopropyl-hydrazine in 150 cc. of absolute benzene. J Thereby, 1,2-diisopropyl-hydrazine hydrochloride precipitated. The mixture was refluxed for onehour, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue recrystallized from methanol. The 1-palmitoyl-l,2-diiso propylshydrazine thus obtained melted at 39".

Example 4 A solution of." 3319- g'-. of chloroacetyh chloride in 200" The mixture cc. of absolute benzene was added dropwise, at room temperature and with stirring, to a solution of 70 g. of 1,2- diisopropyl-hydrazine in 1000 cc. of benzene. Thereby, 1,2-diisopropyl-hydrazine hydrochloride precipitated. The mixture was further stirred for some time, then permitted to stand for several hours and filtered by suction. The filtrate was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by distillation in high vacuo. There was thus obtained 1- chloroacetyl-1,2-diisopropyl-hydrazine as a colorless viscous oil boiling at 67/0.03 mm.

Example 5 A solution of 59 g. of1,2-diisopropyl-hydrazine in 1300 cc. of absolute benzene was added dropwise, at room temperature and while stirring, to a solution of 35 g. of a-acetoxypropionic acid chloride in 200 cc. of absolute benzene. The mixture was stirred for an additional 1-2 hours and then permitted to stand overnight. The precipitated 1,2-diisopropyl-hydrazine hydrochloride was filtered by suction, the filtrate washed with water, dried over sodium sulfate and concentrated in vacuo. The oily residue which rapidly solidified was recrystallized from high boiling petroleum ether. The l-a-acetoxypropionyl- 1,2-diisopr'opyl-hydrazine obtained melted at 6l-64.

1 cc. of absolute methanolic 2 N sodium methylate solution was added to a solution of g. of l-a-acetoxypropionyl-l,2-diisopropyhhydrazine in 50 cc. of absolute methanol. The mixture was allowed to stand overnight and then concentrated in vacuo. The oily residue was taken up in ether, the ethereal solution washed with a saturated sodium chloride solution, dried and concentrated. The oily residue rapidly solidified. Upon recrystallization from petroleum ether, the l-a-hydroxypropionyl-1,2-diisopropyl-hydrazine obtained melted at 65-67.

Example 6 A solution of 10.8 g. of methoxyacetyl chloride in 50 cc. of absolute benzene was added dropwise over a period of 2 /2 hours, at room temperature and while stirring, to a solution of 25.5 g. of 1,2-diisopropyl-hydrazine in 350 cc. of absolute benzene. Thereby, l,2-diisopropyl-hydrazine hydrochloride precipitated. The mixture was stirred for an additional 4 hours at 40, then cooled to room temperature and filtered. The filtrate was washed with a saturated sodium chloride solution and with a saturated sodium bicarbonate solution, dried over soduim sulfate and concentrated. The residue was purified by fractionating in vacuo. l-methoxy-acetyl-1,2-diisopropylhydrazine was thus obtained as a colorless oil boiling at 109110/ 12 mm; n =1.4525; which solidified on standing at room temperature.

Example 7 consisted of l-methoxyacetyl-l,2-diisopropyl-hydrazine. It solidified on standing at room temperature.

Example 8 A solution of 12.5 g. of methylrnercaptoacetyl chloride in 100 cc. of benzene was added dropwise, while stirring, to asolution of 32 g. of 1,2-diisopropyl-hydrazine in 150 cc. of benzene. The mixture was refluxed for one hour, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue purified by distillation. The 1-methylmercaptoacetyl-1,2-diisopropylhydrazine thus obtained boiled at 126l28/l2 mm; n =1.4855.

Example 9 Example 10 A solution of 14.6 g. of cyclohexanecarboxylic acid chloride in 50 cc. of absolute benzene was added dropwise over a period of 2 /2 hours, at room temperature and while stirring, to a solution of 25.5 g. of 1,2-diisopropylhydrazine in 450 cc. of absolute benzene. The mixture was stirred for an additional 4 hours at 40, then cooled to room temperature and filtered. The filtrate was washed with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by distillation in vacuo. There was thus obtained l-cyclohexanecarbonyb1,2-diisopropyl-hydrazine as a colorless oil boiling at 65/ 0.06 mm.; it solidified on standing at room temperature.

We claim:

1. A hydrazine derivative of the formula UDE-t):

wherein R represents a member of the group consisting l-chloroacetyl-1,2-diisopropyl-hydrazine. A hydrazine derivative of the formula C H 0 H3) 7 Lower alkanoyloiry-lower alkyl-C O-NNHCH (CH3); l0. l-a-acetoxypropionyl-l,Z-diisopropyl-hydrazine. 11. A hydrazine derivative of the formula HydroXy-lower alkyl-C ONNHO H (0 Hz) 2 12. l-m-hydroxypropionyl-l ,2-diisopropyl-hydrazine. 13. A hydrazine derivative of the formula C H (CH3) 2 Lower alkoxy-Iower allryl-O 0--N-NHOH (0 Ha) 14. l-methoxyacetyll,2-cliisopropylhydrazine. 15. A hydrazine derivative of the formula C H (0 H3) 2 Lower alkylmereapto-lower allryl-C ONNH-CH (CH3);

5 6 16. l-methylmercaptoacetyl-1,2-diisopropyl-hydrazine. References Cited in the file of this patent 17. A hydrazine derivative of the formula UNITED STATES PATENTS OH(O a)= 2,835,703 Caldwell et a1 May 20, 1958 Gycloalkyl-CO-N-NHOH(CH3)2 5 OTHER REFERENCES wherein the cyoloalkyl group contains 3 to 6 carbon Lochte et a1.: J.A.C.S., vol. 43 (1921), pp. 2597 to atoms. 2603. I

18. 1-cyclopropanecarbonyl-1,2-diisopropyl-hydrazine. Ralston: Fatty Acids and Their Derivatives (1948), p.

19. l-cyclohexanecarbonyl-l,Z-diisopropyl-hydrazine. 309. 

1. A HYDRAZINE DERIVATIVE OF THE FORMULA 